It has been discovered that in vivo production of acrolein may cause and/or exacerbate pain, such as pain due to disease or injury. It has also been discovered herein that compounds capable of interacting with acrolein are efficacious in treating pain. Without being bound by theory, it is believed herein that compounds that are capable of scavenging and/or preventing acrolein from activating pain relay systems, such as those found on dorsal root ganglion, and other sensory neurons, are efficacious in treating pain. Further, and without being bound by theory, it is believed herein that the compounds described herein capable of blocking the interaction of acrolein with pain relay receptors, such as Transient Receptor Potential Ankyrin 1 (TRPA1), are efficacious in treating pain. In particular, the invention described herein pertains to the treatment of pain using compounds that decrease and/or block the action of ligands and antagonists.
Acrolein, a reactive α,β-unsaturated aldehyde, has been reported to be a product of oxidative stress and lipid peroxidation. Furthermore, acrolein has been reported to remain active in the body for several days (Ghilarducci and Tjeerdema, 1995) while more commonly studied oxidative species decay within seconds (Halliwell and Gutteridge, 1999). Described herein is the role of acrolein in the pain using a well-established animal model of injury.
It has also been discovered that hydrazinopyridazines, fused hydrazinopyridazines, phenylethylhydrazines, and combinations thereof are useful in treating pain caused by disease and/or injury. Illustrative disease based pain includes allodynia, pain associated with MS, pain associated with neuropathy, such as pain associated with diabetes, and the like. Illustrative injury based pain includes neuronal injury such as spinal cord injury (SCI), spinal cord contusion injury, and the like. Additional illustrative disease-based pain or injury-based pain includes inflammatory pain, cancer pain, postoperative pain, and idiopathic pain (i.e. pain of unknown origin), for example, phantom limb pain. In one aspect, neuropathic pain includes pain caused by injury or infection of peripheral sensory nerves. Illustrative examples of neuropathic pain include, but are not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain includes, but is not limited to pain caused by nerve injury such as, for example, the pain diabetics suffer from. It has also been discovered that the compounds described herein are useful in decreasing or blocking the action of acrolein at TRPA1. Without being bound by theory, it is believed herein that the ligand binding properties, and more importantly the agonist properties of acrolein are decreased or by the compounds described herein. It has been discovered herein that injury may upregulate acrolein production, illustratively neuronal injury such as spinal cord injury (SCI), and the pain caused thereby is mediated by acrolein production. It has been discovered that the compounds described herein are capable of decreasing or blocking the pain associated with acrolein, including increased acrolein production following injury.
In one illustrative embodiment of the invention, compounds of the following formula are described herein:
and pharmaceutically acceptable salts thereof, wherein:
R is independently selected in each instance from hydrogen, acyl, or sulfonyl; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and
RA represents three substituents selected from the group consisting of hydrogen, halo, hydroxy and derivatives thereof, amino and derivatives thereof, thio and derivatives thereof, acyl, carboxylate or a derivative thereof, hydroxylamino and derivatives thereof, hydrazino and derivatives thereof, sulfinyl or a derivative thereof, or sulfonyl or a derivative thereof; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or two of RA are taken together with the attached carbons to form an optionally substituted saturated, unsaturated, or aromatic carbocycle or heterocycle.
In one illustrative embodiment of the invention, compounds of the following formula are described herein:
and pharmaceutically acceptable salts thereof, wherein:
R is independently selected in each instance from hydrogen, acyl, or sulfonyl; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; and
RA represents three substituents selected from the group consisting of hydrogen, halo, hydroxy and derivatives thereof, amino and derivatives thereof, thio and derivatives thereof, acyl, carboxylate or a derivative thereof, hydroxylamino and derivatives thereof, hydrazino and derivatives thereof, sulfinyl or a derivative thereof, or sulfonyl or a derivative thereof; or alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heteroalkyl, heteroalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted; or two of RA are taken together with the attached carbons to form an optionally substituted saturated, unsaturated, or aromatic carbocycle or heterocycle.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating pain in a patient. It is to be understood that the compositions may include other component and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating patients having pain are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to a patient having pain. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients having pain. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients having pain are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient having pain. In another embodiment, unit doses and/or unit dosage forms that include the compounds and pharmaceutical compositions for treating patients having pain are also described herein. In another aspect, the unit doses and/or unit dosage forms are administered to a patient having pain.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating pain, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms that may accompany or be accompanied by pain.
Hydralazine, a fused hydrazinopyridazine, is an illustrative compound that may be included in the pharmaceutical compositions, unit dosage forms, methods, and uses described herein. Hydralazine is an effective acrolein scavenger and is used to trap acrolein, which is significantly increased following injury. Hydralazine treatment appears to alleviate pain, and tends to lower acrolein levels in injured tissue, such as spinal cord. Without being bound by theory, it is believed herein that the ability of hydralazine to treat pain is due at least in part to its capability of interacting with, blocking, or otherwise intervening in the pathology of acrolein. Additional illustrative hydrazinopyridazines and fused hydrazinopyridazines useful in the methods, uses, formulations, and unit dosage forms described herein include, but are not limited to:
and analogs and derivatives thereof.